US4166861A - Pharmacologically active polyphenolic substances - Google Patents

Pharmacologically active polyphenolic substances Download PDF

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Publication number
US4166861A
US4166861A US05/780,171 US78017177A US4166861A US 4166861 A US4166861 A US 4166861A US 78017177 A US78017177 A US 78017177A US 4166861 A US4166861 A US 4166861A
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United States
Prior art keywords
catechin
penta
epicatechin
acetylferulate
chlorophenoxy
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Expired - Lifetime
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US05/780,171
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English (en)
Inventor
Attilio Bonati
Giuseppe Mustich
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Inverni Della Beffa SpA
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Inverni Della Beffa SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • This invention relates to pharmacologically active polyphenolic substances and to processes for their production.
  • Catechin (I) and epicatechin (II) are polyphenolic substances which are widely distributed in nature ##STR1##
  • epicatechin and certain novel derivatives of catechin and of epicatechin possess remarkable choleretic, hypocholesterolemic, hypolipaemic and hepatoprotective activity and are of relatively low toxicity.
  • compositions comprising epicatechin and/or one or more pharmaceutically acceptable ketals or esters of catechin or of epicatechin and a pharmaceutically acceptable diluent or carrier.
  • the esters and ketals of catechin and epicatechin may have the general formulae III or IV ##STR2## wherein in formula III R 1 , R 2 and R 3 each represent a hydrogen atom or an acyl group and R 4 and R 5 each represent a lower alkyl group (as hereafter defined), and in formula IV, at least one of R 1 , R 2 , R 3 , R 6 and R 7 represents an acyl group and each of the others represents an acyl group or a hydrogen atom, and such esters and ketals form a further aspect of the present invention.
  • acyl radicals represented by R 1 , R 2 , R 3 , R 6 and R 7 may be derived from acids of the formula RCOOH where R is an alkyl or substituted alkyl group, aryl or substituted aryl group, aralkyl or substituted aralkyl group, aralkenyl or substituted aralkenyl groups or heterocyclic group.
  • the acid should not contain more than 20 and preferably not more than 15 carbon atoms.
  • the substituted or unsubstituted alkyl groups represented by R should be substituted or unsubstituted lower alkyl groups by which are meant alkyl groups containing 1 to 8 carbon atoms, e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, and such groups may be straight chained as in n-butyl, branched as in iso-propyl or cyclic as in cyclohexyl.
  • alkyl and alkenyl constituents of the substituted and unsubstituted aralkyl and aralkenyl groups should be derived from lower alkyl and lower alkenyl groups wherein the term "lower" is as defined above.
  • aryl groups represented by R and also the aryl constituents of the aralkyl and arakenyl groups are preferably phenyl. These aryl groups may themselves be substituted by one or more alkyl groups as defined above.
  • Heterocyclic groups represented by R may, for example, be nitrogen-containing heterocyclic groups, such as pyridyl.
  • RCOOH examples include halogen, hydroxy, alkoxy (and preferably lower alkoxy groups derived from the lower alkyl groups defined above), and esterified hydroxy, particularly hydroxy esterified with an acid R 1 COOH wherein R 1 is lower alkyl as defined above.
  • a particularly preferred class of compounds according to the invention are those in which one or more of the acyl radicals represented by R 1 , R 2 , R 3 , R 6 and R 7 are derived from acids which in free or esterified form possess choleretic, hypocholesterolemic or hypolipaemic activity.
  • acids which in free or esterified form possess choleretic, hypocholesterolemic or hypolipaemic activity.
  • acids are nicotinic acid, caffeic acid, acetylferulic acid and 2-(p-chlorophenoxy)-2-methyl propionic acid.
  • the compounds of formulae III and IV which are esters may be prepared according to a further aspect of the invention by reacting catechin, epicatechin or a ketal of catechin or of epicatechin with an appropriate acylating agent, for example an acid anhydride or acyl chloride, preferably in the presence of a polar aprotic solvent such as, for example, pyridine or dioxan.
  • an appropriate acylating agent for example an acid anhydride or acyl chloride
  • a polar aprotic solvent such as, for example, pyridine or dioxan.
  • compounds of formula III may be prepared from catechin, from epicatechin, or from a compound of formula IV in which R 6 and R 7 are hydrogen by reaction with a ketone in the presence of an acid catalyst.
  • the present invention includes pharmaceutical compositions comprising epicatechin and/or one or more pharmaceutically acceptable ketals or esters of catechin or of epicatechin and a pharmaceutically acceptable carrier.
  • the invention also provides methods for producing such compositions which comprise bringing the afore-mentioned active ingredients into a form suitable for administration, for example by mixing with a pharmaceutically acceptable excipient.
  • compositions of the invention depends on the intended route of administration and such forms may be amorphous or in the form of shaped dosage units.
  • examples include sterile liquids suitable for parenteral administration and forms suitable for oral administration (e.g. tablets, capsules, comfits, solutions or suspensions).
  • compositions according to the invention a wide range of excipients may be used, the nature of which will depend, of course, on the intended mode of application of the composition. Examples include preservatives and buffering, thickening, suspending, stabilising, wetting, emulsifying, colouring and flavouring agents.
  • excipients include carboxy vinyl polymers, propylene glycol, ethyl alcohol, water, cetyl alcohol, saturated vegetable triglycerides, fatty acid esters or propylene glycol, triethanolamine, glycerol, starch, lactose, sucrose, cellulose sorbitol, bentonite, cellulose, methylcellulose, carboxymethyl cellulose, lauryl-sulphate, dicalcium phosphate, powdered silica, titanium dioxide, lecithin, magnesium carbonate, magnesium stearate etc.
  • catechin 1.8 g. were dissolved in 30 ml. of dioxan. This solution was poured into a suspension of 6 g. thionyl caffeic acid chloride in 20 ml. of pyridine. The mixture was left to react overnight at room temperature and was then poured with agitation into 500 ml. of water at 4°-5° C.
  • the choleretic activity was determined in accordance with the technique described by R. Lambert in "Surgery of the Digestive System in the Rat” 1965. Sprague Dawley rats of mean weight of 230 g. were used. The products were injected intraperitoneally at the dosage of 100 mg/kg., the volume of the bile and the corresponding dry residue being measured then from 1 hour to 4 hours after administration. Epicatechin and catechin peracetylferulate were found to increase the volume of the bile by 38% and 64% respectively and increase the dry residue of the bile by 35% and 36% respectively, in comparison with the basal values. These increases are significant.
  • the hyperlipaemic activity was determined in Sprague Dawley rats of mean weight of 160 g., in which hyperlipaemia was induced by means of administration of 20 ml./kg. of olive oil orally in animals which had been fasting for 16 hours. Two treatments were effected with the products under examination (upon groups of 18 animals), the first two hours before the olive oil, the second two hours afterwards. The doses were administered orally and were equal to 100 mg./kg. The rats were slaughtered two hours after the final treatment and the triglycerides in the plasma were measured by the colorimetric method of SIGMA CHEM Co. It was found that epicatechin and pernicotinylcatechin significantly diminished the concentration of the triglycerides in the plasma by 42% and 27% respectively in comparison with the controls.
  • Hyperlipaemia was induced by endovenous administration of 225 mg./kg. of Triton WR 1339 dissolved in physiological solution to Sprague Dawley rats of mean weight of 200 g. which had been fasting for 24 hours.
  • the products under examination were injected intraperitoneally at the dosage of 100 mg./kg. of which 50 mg./kg. immediately after the Triton and 50 mg./kg. after 4 hours. After a further 4 hours the animals were slaughtered and the cholesterol and triglycerides in the plasma were measured.
  • pernicotinylcatechin and peracetylcatechin significantly diminish the concentration of cholesterol by 21.1% and 16.3% respectively and that of the triglycerides by 28.7% and 23.1% respectively, in comparison with the controls.
  • choleretic activities of catechin and epicatechin were determined in the manner described in paragraph A above except that the substances under test were administered per os at the rate of 200 mg./kg.
  • catechin pentacetyl ferulate has a marked choleretic action when administered orally as determined by measurement of bile volume and the dry residue content thereof three hours after treatment, while catechin displays no statistically significant choleretic effect.
  • the hypolipaemic activity of catechin and epicatechin was determined in the manner described in paragraph B1 above.
  • epicatechin has a marked hypolipaemic effect, whereas catechin has no statistically significant hypolipaemic effect when administered under similar conditions.
  • compositions according to the invention exemplify pharmaceutical compositions according to the invention:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US05/780,171 1976-03-23 1977-03-22 Pharmacologically active polyphenolic substances Expired - Lifetime US4166861A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB11666/76A GB1575004A (en) 1976-03-23 1976-03-23 Pharmacologically active polyphenolic substances
GB11666/76 1976-03-23

Publications (1)

Publication Number Publication Date
US4166861A true US4166861A (en) 1979-09-04

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Country Status (10)

Country Link
US (1) US4166861A (fr)
JP (1) JPS52116473A (fr)
BE (1) BE852741A (fr)
CH (2) CH633289A5 (fr)
DE (1) DE2711927A1 (fr)
ES (1) ES457091A1 (fr)
FR (1) FR2345441A1 (fr)
GB (1) GB1575004A (fr)
GR (1) GR59771B (fr)
PT (1) PT66301B (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4248789A (en) * 1979-02-07 1981-02-03 Director Of National Research Institute Of Tea Process for producing catechins
US4285964A (en) * 1979-08-30 1981-08-25 Continental Pharma Salts of (+)-catechine, their preparation and use, and compositions containing these salts
US4510159A (en) * 1982-06-01 1985-04-09 Zyma Sa (+)-Cyanidan-3-ol derivatives, pharmaceutical preparations that contain such compounds, and the use of the latter to treat liver or venous diseases
US4617296A (en) * 1977-11-25 1986-10-14 Ciba-Geigy Corporation 3-O-acylated derivatives of (+)-cyanidan-3-ol
US4644011A (en) * 1982-06-01 1987-02-17 Zyma Sa Pharmaceutical preparations containing (+)-cyanidan-3-ol derivatives, the use thereof, novel substituted (+)-cyanidan-3-ol derivatives, and processes for producing them
WO1987006128A1 (fr) * 1986-04-07 1987-10-22 Clemetson Ab Charles Acide ascorbique revetu de catechine, et procede d'obtention
US4760088A (en) * 1986-09-15 1988-07-26 Board Of Control Of Michigan Technological University Biocidal derivatives of catechins
US4906656A (en) * 1986-09-15 1990-03-06 Board Of Control Of Michigan Technological University Biocidal treatment of materials with catechins
US5527552A (en) * 1993-04-01 1996-06-18 Kalamazoo Holdings, Inc. Lipid-soluble green tea catechin antioxidant solutions
WO1997036497A3 (fr) * 1996-04-02 1997-12-24 Mars Inc Composes d'extraits de cacao et leurs procedes de fabrication et d'utilisation
US5844061A (en) * 1993-06-14 1998-12-01 Berkem Polyphenol derivative compositions and perparation thereof
EP0815857A4 (fr) * 1995-12-26 2001-04-04 Suntory Ltd Agent anti-obesite dont le principe actif est la procyanidine
US6261565B1 (en) * 1996-03-13 2001-07-17 Archer Daniels Midland Company Method of preparing and using isoflavones
US6297273B1 (en) 1996-04-02 2001-10-02 Mars, Inc. Use of cocoa solids having high cocoa polyphenol content in tabletting compositions and capsule filling compositions
US6423743B1 (en) 1996-04-02 2002-07-23 Mars Incorporated Cocoa extract compounds and methods for making and using the same
US6469053B1 (en) 1996-04-02 2002-10-22 Mars Incorporated Use of procyanidins in the maintenance of vascular health and modulation of the inflammatory response
US20040097432A1 (en) * 2002-11-04 2004-05-20 Access Business Group International Llc. Method of reducing cholesterol
KR100504119B1 (ko) * 2001-04-23 2005-07-27 한국생명공학연구원 간염 예방 또는 치료용 약학적 조성물
AU2005203665B2 (en) * 1996-04-02 2008-06-26 Mars, Incorporated Cocoa extract compounds and methods for making and using the same
WO2012159639A1 (fr) * 2011-05-24 2012-11-29 Younes Abdel Khalek Hassan Complément alimentaire pour thérapie du virus de l'hépatite c
CN104327033A (zh) * 2014-09-30 2015-02-04 浙江大学 3’和4’-酯基儿茶素分子选择性制备方法
CN108129438A (zh) * 2017-12-25 2018-06-08 中国海洋大学 一种含2-苯色满母核的化合物及其制备方法

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3176349D1 (en) * 1980-04-03 1987-09-17 Zyma Sa Use of o-substituted derivatives of (+)-cyanidanol-3 as compounds with immunomodulative properties
JPS60156614A (ja) * 1984-01-26 1985-08-16 Mitsui Norin Kk コレステロ−ル上昇抑制剤
JPH09291039A (ja) * 1995-12-26 1997-11-11 Suntory Ltd プロシアニジンを有効成分とする抗肥満剤
WO1998011889A1 (fr) * 1996-09-18 1998-03-26 Marigen S.A. Ultramicroemulsions composees de concentres a dispersion spontanee renfermant des esters de composes de bioflavonoide a action antitumorale, antivirale, virucide et antiparasitaire
JP2006104213A (ja) * 2003-02-10 2006-04-20 Ito En Ltd 血清コレステロールを低下させるために用いる飲食物およびその製造方法
JP2006232752A (ja) * 2005-02-25 2006-09-07 Tokyo Univ Of Marine Science & Technology コレステロール及び中性脂肪吸収抑制剤及びこれを含む食品
JP2013528574A (ja) * 2010-04-12 2013-07-11 ベルケム エス．ア． 安定化ポリフェノール誘導体、その生産方法、及びその使用
WO2015163062A1 (fr) * 2014-04-23 2015-10-29 日本製紙株式会社 Agent de prévention ou d'amélioration du diabète

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1057349A (en) * 1965-01-29 1967-02-01 Merck Ag E Water-soluble flavanoid derivatives
FR7941M (fr) * 1967-05-23 1970-05-25
US3546250A (en) * 1966-08-18 1970-12-08 Merck Ag E 6-hydroxy-7-methoxy flavane derivatives and esters thereof
FR2073251A1 (en) * 1969-12-03 1971-10-01 Therapeuti Bureau Et Flavanol polyacid complexes - useful for stabilizing and purifying flavanol monomers for antiscorbutic use
FR2128207A1 (fr) * 1971-03-11 1972-10-20 Zyma Sa

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1057349A (en) * 1965-01-29 1967-02-01 Merck Ag E Water-soluble flavanoid derivatives
US3546250A (en) * 1966-08-18 1970-12-08 Merck Ag E 6-hydroxy-7-methoxy flavane derivatives and esters thereof
FR7941M (fr) * 1967-05-23 1970-05-25
FR2073251A1 (en) * 1969-12-03 1971-10-01 Therapeuti Bureau Et Flavanol polyacid complexes - useful for stabilizing and purifying flavanol monomers for antiscorbutic use
FR2128207A1 (fr) * 1971-03-11 1972-10-20 Zyma Sa

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Vitaminy, Akademiya Nauk Ukrainskoi SSR., Inst. Biokhimii, vol. 3, 1958, pp. 50-59. *

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4617296A (en) * 1977-11-25 1986-10-14 Ciba-Geigy Corporation 3-O-acylated derivatives of (+)-cyanidan-3-ol
US4248789A (en) * 1979-02-07 1981-02-03 Director Of National Research Institute Of Tea Process for producing catechins
US4285964A (en) * 1979-08-30 1981-08-25 Continental Pharma Salts of (+)-catechine, their preparation and use, and compositions containing these salts
US4510159A (en) * 1982-06-01 1985-04-09 Zyma Sa (+)-Cyanidan-3-ol derivatives, pharmaceutical preparations that contain such compounds, and the use of the latter to treat liver or venous diseases
US4644011A (en) * 1982-06-01 1987-02-17 Zyma Sa Pharmaceutical preparations containing (+)-cyanidan-3-ol derivatives, the use thereof, novel substituted (+)-cyanidan-3-ol derivatives, and processes for producing them
AU569033B2 (en) * 1982-06-01 1988-01-21 Zyma S.A. (+)-cyanidan-3-ol derivatives
WO1987006128A1 (fr) * 1986-04-07 1987-10-22 Clemetson Ab Charles Acide ascorbique revetu de catechine, et procede d'obtention
US4760088A (en) * 1986-09-15 1988-07-26 Board Of Control Of Michigan Technological University Biocidal derivatives of catechins
US4906656A (en) * 1986-09-15 1990-03-06 Board Of Control Of Michigan Technological University Biocidal treatment of materials with catechins
US5527552A (en) * 1993-04-01 1996-06-18 Kalamazoo Holdings, Inc. Lipid-soluble green tea catechin antioxidant solutions
US5844061A (en) * 1993-06-14 1998-12-01 Berkem Polyphenol derivative compositions and perparation thereof
US6294190B1 (en) 1995-12-26 2001-09-25 Suntory Limited Antiobestic agent containing procyanidin as the active ingredient
KR100896914B1 (fr) * 1995-12-26 2009-07-28
EP0815857A4 (fr) * 1995-12-26 2001-04-04 Suntory Ltd Agent anti-obesite dont le principe actif est la procyanidine
US20030064938A1 (en) * 1996-03-13 2003-04-03 Mark Empie Method of preparing and using compositions extracted from vegetable matter for the treatment of cardiovascular conditions
US6261565B1 (en) * 1996-03-13 2001-07-17 Archer Daniels Midland Company Method of preparing and using isoflavones
US6900240B2 (en) 1996-03-13 2005-05-31 Archer-Daniels-Midland Company Method of preparing and using compositions extracted from vegetable matter for the treatment of cancer
AU742198B2 (en) * 1996-04-02 2001-12-20 Mars, Incorporated Cocoa extract compounds and methods for making and using the same
US6297273B1 (en) 1996-04-02 2001-10-02 Mars, Inc. Use of cocoa solids having high cocoa polyphenol content in tabletting compositions and capsule filling compositions
US6423743B1 (en) 1996-04-02 2002-07-23 Mars Incorporated Cocoa extract compounds and methods for making and using the same
US6638971B2 (en) 1996-04-02 2003-10-28 Mars, Incorporated Cocoa extract compounds and methods for making and using the same
US6670390B1 (en) 1996-04-02 2003-12-30 Mars Incorporated Cocoa extract compounds and methods for making and using the same
WO1997036497A3 (fr) * 1996-04-02 1997-12-24 Mars Inc Composes d'extraits de cacao et leurs procedes de fabrication et d'utilisation
US6747059B1 (en) 1996-04-02 2004-06-08 Mars, Incorporated Composition for, and methods of, anti-platelet therapy
US6469053B1 (en) 1996-04-02 2002-10-22 Mars Incorporated Use of procyanidins in the maintenance of vascular health and modulation of the inflammatory response
AU2005203665B2 (en) * 1996-04-02 2008-06-26 Mars, Incorporated Cocoa extract compounds and methods for making and using the same
KR100504119B1 (ko) * 2001-04-23 2005-07-27 한국생명공학연구원 간염 예방 또는 치료용 약학적 조성물
US20040097432A1 (en) * 2002-11-04 2004-05-20 Access Business Group International Llc. Method of reducing cholesterol
WO2012159639A1 (fr) * 2011-05-24 2012-11-29 Younes Abdel Khalek Hassan Complément alimentaire pour thérapie du virus de l'hépatite c
CN104327033A (zh) * 2014-09-30 2015-02-04 浙江大学 3’和4’-酯基儿茶素分子选择性制备方法
CN108129438A (zh) * 2017-12-25 2018-06-08 中国海洋大学 一种含2-苯色满母核的化合物及其制备方法

Also Published As

Publication number Publication date
PT66301B (en) 1978-08-10
PT66301A (en) 1977-04-01
FR2345441B1 (fr) 1980-10-10
DE2711927A1 (de) 1977-10-06
CH633289A5 (de) 1982-11-30
FR2345441A1 (fr) 1977-10-21
ES457091A1 (es) 1978-08-16
BE852741A (fr) 1977-07-18
GR59771B (en) 1978-02-25
GB1575004A (en) 1980-09-17
JPS52116473A (en) 1977-09-29
CH635093A5 (de) 1983-03-15

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